PROJECT SUMMARY/ABSTRACT Aging drives regenerative and cognitive impairments in the adult brain increasing susceptibility to dementia- related neurodegenerative diseases, such as Alzheimer's disease, in healthy individuals. Evidence suggests that exercise can counter age-related decline in regenerative capacity and cognition in the aged brain. The ability to reverse brain aging through systemic interventions such as exercise could enable the mitigation of vulnerability to age-related neurodegenerative diseases, fulfilling an unmet need that is growing more pressing as the human population ages. Despite the evident benefit of exercise, its application is hindered in the elderly by technical barriers, with evidence that perception of physical frailty or poor health alone can decrease adherence. Therefore, it is critical to identify accessible therapeutic approaches that confer benefits of exercise while circumventing pre-existing limitations. We and others have previously shown that systemic manipulations, including heterochronic parabiosis (in which the circulatory system of a young and old animal are joined) and young blood plasma administration, likewise enhance adult neurogenesis and cognition in aged mice1,3,13. The rejuvenating effects observed with exercise mirror those of a youthful circulation, raising the possibility that exercise similarly functions through blood factors to exert its beneficial effects. Indeed, preliminary data from our lab demonstrate that systemic administration of blood plasma derived from exercised mice reverses age-related impairments in adult neurogenesis and cognition in aged mice. The purpose of the proposed study is thus to investigate the rejuvenating and therapeutic effects of exercise-induced blood factors on the aged brain. Specifically, our hypothesis is that systemic exposure to exercise-induced blood factors elicits long lasting rejuvenation of regenerative and cognitive functions, while ameliorating neurodegenerative phenotypes. We will test this theory with Three Specific Aims: 1: Characterize the kinetics of brain rejuvenation following systemic exposure to exercise-induced blood factors. 2: Investigate the role of the exercise-induced blood factor Gpld1 in rejuvenating the aged brain. 3: Determine the therapeutic potential of exercise-induced blood factors in a mouse model of Alzheimer's disease. Successful completion of these studies will have significant translational potential, identifying molecular and cellular pathways that could be targeted for novel therapies to ameliorate dementia-related neurodegenerative diseases such as Alzheimer's disease.